Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic telangiectases associated with recurrent hemorrhage leading to serious morbidity and 10% mortality. Endoglin, a TGF-Beta receptor on endothelial cells, has been identified as the type 1 HMT gene. Its role in HHT is unknown. The localized but random distribution of the telangiectases coupled with the increase in size and number of lesions with age suggests that endoglin requires a secondary somatic mutation for expression of the mutant phenotype. We hypothesize that HHT, although inherited as an autosomal dominant disorder, exhibits a cellular-recessive pathology and requires inactivation of the wild-type allele as the initiating event in the formation of a lesion. Furthermore, we hypothesize that endoglin acts like a tumor suppressor gene in suppressing angiogenesis and that disruption of the endoglin gene results in disordered angiogenesis at the site of the lesion. Four specific aims will be addressed. (1) Endoglin Expression in HHT lesions will be assessed using immunohistochemistry. (2) TGF-Beta binding to HHT Lesions will be assessed by ligand binding on tissue sections. (3) Identification of Secondary Somatic Mutations or Loss of Heterozygosity in HHT Lesions will be determined by PCR of microdissected HHT lesions. (4) Cultured Endothelial Cells will be transfected with sense and antisense endoglin RNA constructs and growth changes and characteristics observed.